Clinical and experimental pediatrics · 2026
Prognosis of pediatric hepatic Wilson disease with ATP7B loss of function variants.
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Mishra Amresh Kumar, Sarma Moinak Sen, Dubey Anchal, Gadekar Pratik, Moirangthem Amita, Srivastava Anshu, Mathias Amrita
Аннотация
BACKGROUND: Genotype-phenotype correlations in Wilson disease (WD) have so far been inconclusive.
PURPOSE: ATP7B variants with loss of function (LOF) may have a different trajectory. Since genotypes in Asia differ from the West, we aimed to correlate LOF variants of ATP7B with the severity and outcome of hepatic WD.
METHODS: Patients with a confirmed diagnosis of WD (Leipzig criteria ≥4) were prospectively enrolled. Genetic sequencing of ATP7Bmutations was assessed by Whole-exome sequencing. For patients with variants of uncertain significance, Sanger sequencing was additionally performed on their parents to identify the inherited variants. In silico analyses were used to predict the pathogenicity of variants. Mutations that resulted in at least one truncation (nonsense, frameshift, splice site, deletions) and nontruncation (missense, synonymous) protein were defined as LOF and no LOF (NLF) respectively. Phenotypes, biochemical parameters, and outcomes were analyzed.
RESULTS: One hundred sixteen hepatic WD children (84 boys, median age at diagnosis 8.9±3.3 years) with biallelic ATP7B mutations (62 different variants) were enrolled. The most common LOF (n=79) and NLF (n=37) variants were c.813C>A and c.3809A>G. Advanced liver disease (76% vs. 4%, P=0.004), portal hypertension (44% vs. 24%, P=0.03), neurological (39% vs. 16%, P=0.01) and renal involvement (44% vs. 13%, P=0.01) were significantly higher in LOF than in NLF. c.813C>A had higher serum exchangeable copper (6.8±4.4 μmol/L vs. 1.4±3.5 μmol/L, P=0.04) and lower disappearance of the Kayser-Fleischer ring (4% vs. 49%, P= 0.01) than c.3809A>G variants. Over a follow-up of 6.1±4.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants.
CONCLUSION: A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement. LOF variants did not affect liver or overall outcomes.
PURPOSE: ATP7B variants with loss of function (LOF) may have a different trajectory. Since genotypes in Asia differ from the West, we aimed to correlate LOF variants of ATP7B with the severity and outcome of hepatic WD.
METHODS: Patients with a confirmed diagnosis of WD (Leipzig criteria ≥4) were prospectively enrolled. Genetic sequencing of ATP7Bmutations was assessed by Whole-exome sequencing. For patients with variants of uncertain significance, Sanger sequencing was additionally performed on their parents to identify the inherited variants. In silico analyses were used to predict the pathogenicity of variants. Mutations that resulted in at least one truncation (nonsense, frameshift, splice site, deletions) and nontruncation (missense, synonymous) protein were defined as LOF and no LOF (NLF) respectively. Phenotypes, biochemical parameters, and outcomes were analyzed.
RESULTS: One hundred sixteen hepatic WD children (84 boys, median age at diagnosis 8.9±3.3 years) with biallelic ATP7B mutations (62 different variants) were enrolled. The most common LOF (n=79) and NLF (n=37) variants were c.813C>A and c.3809A>G. Advanced liver disease (76% vs. 4%, P=0.004), portal hypertension (44% vs. 24%, P=0.03), neurological (39% vs. 16%, P=0.01) and renal involvement (44% vs. 13%, P=0.01) were significantly higher in LOF than in NLF. c.813C>A had higher serum exchangeable copper (6.8±4.4 μmol/L vs. 1.4±3.5 μmol/L, P=0.04) and lower disappearance of the Kayser-Fleischer ring (4% vs. 49%, P= 0.01) than c.3809A>G variants. Over a follow-up of 6.1±4.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants.
CONCLUSION: A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement. LOF variants did not affect liver or overall outcomes.